MICROCYSTINS, NATURAL ENVIRONMENTAL TOXINS

微囊藻毒素，天然环境毒素

• 批准号: 3253963
• 负责人: MARIA T RUNNEGAR
• 金额: $ 20.99万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3253963
• 关键词: Cyanophyta; NAD(H) phosphate; autoradiography; calcium flux; cellular pathology; cytoskeleton; cytotoxicity; environmental toxicology; fresh water environment; gel electrophoresis; glutathione; hepatotoxin; high performance liquid chromatography; image processing; immunofluorescence technique; laboratory mouse; laboratory rat; lipid peroxides; liver function; liver toxic disorder; molecular pathology; morphology; nicotinamide adenine dinucleotide; pathology; plant extracts; radionuclides; toxicant interaction; toxin metabolism

The microcystins, a family of related heptapeptides produced by the freshwater bloom-forming cyanobacterium Microcystis aeruginosa are naturally occurring environmental toxins. They are quite potent, (LD(50)ip in mice <O.l mg/kg) and chemically stable; their hepatotoxicity is not lost on boiling, nor are they inactivated by ordinary potable water treatment, thereby posing a threat to public health. An epidemiological study has shown that the presence of toxic peptides in the water supply correlated with increased liver damage in the population. Although the liver lesions caused by microcystin have been well described, the mechanism by which these peptide toxins act at the molecular or cellular level is not known. The overall purpose of this proposal is to elucidate the mechanism by which the microcystins cause liver damage. The specific work planned follows from the work done by the PI in Australia. It is known that microcystin is taken up by isolated hepatocytes, and that when administered to animals, it rapidly accumulates in the liver. (1) It is planned here to look at the transport, distribution (particularly intrahepatically), and metabolic fate of the toxin, using the easily prepared and well characterized (125)I-labeled derivative of microcystin. This will be correlated with the pathological changes found in animals following administration of microcystin. (2) The possibility that microcystin toxicity in vivo is mediated by an effect on non-parenchymal liver cells will be studied. Previous work has shown that microcystin causes changes in isolated hepatocytes. From this, two specific aims arise. These are: (3) to study the interaction of microcystin with the cytoskeleton, and (4) to characterize metabolic changes, especially changes in glutathione and calcium homeostasis. A variety of models will be employed: whole animals, isolated perfused livers, freshly isolated and cultured hepatocytes, endothelial cells. The work will be done in the laboratory of the co-PI, where all these models are in use for other liver studies. The results obtained from all these approaches will reconcile the hepatotoxicity in animals of these toxins with the changes the toxins cause in isolated hepatocytes.

微囊藻毒素是由微囊藻毒素产生的一类相关的七肽 淡水水华蓝藻铜绿微囊藻是 自然产生的环境毒素。它们相当强大，(LD(50)IP 对小鼠)和化学稳定性；它们的肝脏毒性不会消失 在沸腾时，它们也不会被普通饮用水处理灭活， 从而对公众健康构成威胁。一项流行病学研究发现 表明供水中有毒多肽的存在与 随着人群中肝脏损伤的增加。尽管肝脏病变 由微囊藻毒素引起的已经被很好地描述了，其机制是 这些多肽毒素在分子或细胞水平上的作用尚不清楚。 这项建议的总体目的是阐明 微囊藻毒素会导致肝脏损伤。计划的具体工作如下 私家侦探在澳大利亚所做的工作。已知微囊藻毒素 由分离的肝细胞上调，当给动物使用时，它 在肝脏中迅速积聚。(1)计划在这里查看 运输、分布(特别是在肝内)和代谢的命运 使用易于制备和良好表征的毒素 (125)I标记的微囊藻毒素衍生物。这将与 给药后动物出现的病理变化 微囊藻毒素。(2)微囊藻毒素体内毒性可能是 所介导的一种对非实质肝细胞的影响将被研究。 先前的工作表明，微囊藻毒素会导致孤立的 肝细胞。由此产生了两个具体目标。这些是：(3)学习 微囊藻毒素与细胞骨架的相互作用，以及(4) 描述代谢变化，特别是谷胱甘肽和 钙稳态。将使用各种模型：完整的动物， 分离的灌流肝脏，新鲜分离和培养的肝细胞， 内皮细胞。这项工作将在联合和平研究所的实验室进行， 所有这些模型都被用于其他肝脏研究。结果是 从所有这些方法获得的将调和肝脏毒性在 动物对这些毒素的变化与毒素引起的隔离 肝细胞。